c-Fms and the αvβ3 integrin collaborate during osteoclast differentiation

Abstract

3 integrin-null osteoclasts are dysfunctional, but their numbers are increased in vivo. In vitro, however, the number of 3 -/-osteoclasts is reduced because of arrested differentiation. This paradox suggests cytokine regulation of 3 -/-osteoclastogenesis differs in vitro and in vivo. In vitro, additional MCSF, but not receptor activator of NF-B ligand (RANKL), completely rescues 3 -/-osteoclastogenesis. Similarly, activation of extracellular signal-regulated kinases (ERKs) and expression of c-Fos, both essential for osteoclastogenesis, are attenuated in 3 -/-preosteoclasts, but completely restored by additional MCSF. In fact, circulating and bone marrow cell membrane-bound MCSFs are enhanced in 3 -/- mice, correlating with the increase in the osteoclast number. To identify components of the MCSF receptor that is critical for osteoclastogenesis in 3 -/-cells, we retrovirally transduced authentic osteoclast precursors with chimeric c-Fms constructs containing various cytoplasmic domain mutations. Normalization of osteoclastogenesis and ERK activation, in 3 -/-cells, uniquely requires c-Fms tyrosine 697. Finally, like high-dose MCSF, overexpression of c-Fos normalizes the number of 3 -/-osteoclasts in vitro, but not their ability to resorb dentin. Thus, while c-Fms and v 3 collaborate in the osteoclastogenic process via shared activation of the ERK/c-Fos signaling pathway, the integrin is essential for matrix degradation.